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BACKGROUND: Human intrastriatal fetal allografts survive over long periods of time in the brains of Parkinson's disease (PD) patients and integrate into host circuitry. However, some grafted patients with a prior history of levodopa-induced dyskinesias have developed off-medication dyskinesias and dystonias following allografting whose mechanism remains poorly understood. The authors present single-unit discharge characteristics in the external and internal globus pallidus (GPe and GPi) in an awake patient with PD undergoing microelectrode-guided surgery for pallidal deep brain stimulation, 10 years following bilateral intraputamenal fetal mesencephalic allografting in an NIH-funded protocol. METHODS: Pallidal single-unit activity at 'rest' and during active movement was evaluated and compared with data sets from 13 PD patients in the 'off-medication' state and from one non-dyskinetic PD patient in the 'on-medication' state. RESULTS AND DISCUSSION: Analysis of firing rate, bursting discharge and oscillatory activity showed that the graft corrected some, but not all, of the abnormalities associated with the off-medication state. Additionally, in the transplanted patient, voluntary hand movement produced a marked reduction in pallidal discharge rate at multiple GPi recording sites, which was not observed during active movement in other patients. These findings are consistent with a persistent effect of transplanted dopamine cells on basal ganglia outflow and suggest a mechanism for the graft-induced dystonic phenotype.

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OBJECTIVE: This article reviews surgical treatments for Parkinson's disease, emphasizing aspects pertinent to family physicians: rationale for and description of surgeries, patient selection issues, and outcome expectations. QUALITY OF EVIDENCE: No published series describes long-term follow up of a randomized controlled study of any surgery for Parkinson's disease. Some reports, however, describe thorough but brief follow up of functioning in small numbers of patients following surgery. MEDLINE articles were identified using Parkinson's disease, surgery, pallidotomy, thalamotomy, stimulation, grafting, and transplantation as search words. Articles chosen for this paper described patients with systematic follow up using accepted validated rating scales. MAIN MESSAGE: Reported series show impressive improvements to patients undergoing lesioning, stimulation, and grafting surgery for Parkinson's disease. These patients are typically severely disabled but highly selected, and follow up is brief. Stereotactic lesioning (pallidotomy and thalamotomy), deep brain stimulation (thalamic, and elsewhere) and grafting (striatal) can be performed safely, but results vary greatly among centres. CONCLUSIONS: Certain Parkinson's disease patients might benefit from surgery. Ideal candidates for pallidotomy experience motor fluctuations with disabling levodopa-induced dyskinesias. Tremors resistant to antiparkinsonian medications sometimes respond to thalamotomy or thalamic stimulation. Other parkinsonian syndromes, dementias, and difficulties with gait and balance respond poorly to unilateral pallidotomy. Bilateral deep brain stimulation procedures could benefit "midline" dysfunction.

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In order to launch a new transplantation program for Parkinson's disease (PD), we evaluated the safety and efficacy of fetal ventral mesencephalic grafts in 3 patients with advanced PD. Inclusion criteria and clinical evaluation followed strictly the Core Assessment Program for Intracerebral Transplantation. The transplantation procedure was based on the technique previously described by the groups in Lund (Sweden) and Créteil (France). The putamen contralateral to the site of predominant symptoms was unilaterally grafted in all patients. Magnetic resonance (MR)-based stereotactic guidance with multiplanar correlation was used to define 3 implantation trajectories in the precommissural, commissural, and postcommissural putamen. Fetal ventral mesencephalon was prepared from 6- to 8-week-old human embryos obtained from same-day abortions. Under general anesthesia, 8 deposits of 3 microliters of the fetal tissue were placed 1 mm apart along each implantation trajectory using a customized microsyringe and needle attached to the stereotactic frame. The patients recovered uneventfully from the neurosurgical procedure. Early postoperative MR clearly showed the implantation trajectories reaching the putamen in all patients. The follow-up period was of 12, 9 and 6 months, for each of the 3 patients, respectively. Clinical changes appeared between 3 and 6 months after transplantation and consisted of an increase in the 'on' periods and in quantitative bilateral improvement in the motor timed tests. There was an improvement of the Unified Parkinson's Disease Rating Scale score and an improvement of rigidity. Tremor was unchanged, and there was a slight and transient increase in dyskinesias. Neuropsychological follow-up revealed slight frontal alterations in 2 patients. Positron emission tomography demonstrated an increase of 18F-fluorodopa uptake in the grafted site. Adverse events include a reversible Cushing syndrome secondary to immunosuppression in 1 patient and a transient episode of confusion in another. The results of this study, designed as a prerequisite for a wider transplantation program, are in accordance with those previously reported by others and show that, using standardized neurosurgical techniques and methods of evaluation, transplantation is a reproducible and safe therapeutic approach which provides clinical benefits to patients with advanced PD.

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NTera-2 (NT2) cells are a human embryonal carcinoma (EC) cell line derived from a teratocarcinoma that differentiate exclusively into postmitotic neurons in vitro following retinoic acid (RA) treatment. Like other EC cell lines, NT2 cells rapidly form lethal tumors following transplantation into peripheral sites or many regions of the brain. However, when grafts are confined to the caudoputamen (CP), the NT2 cells differentiate into postmitotic neuronlike cells and do not form lethal tumors. To examine the long-term fate of such grafts, we studied NT2 cell transplants in the CP of nude mice that survived for > 1 year. NT2 cells in these grafts acquired molecular markers of fully mature neurons including the low, middle, and high molecular weight neurofilament proteins, microtubule-associated protein 2, tau, and synaptophysin. Furthermore, neuronlike cells in long-term CP grafts formed synaptic structures, and their processes became myelinated, whereas tyrosine hydroxylase (TH)-positive neuronlike cells in the grafts increased with progressively longer postimplantation survival times. Soluble extracts of the adult mouse CP augmented TH expression in RA-treated NT2 cells in vitro. These data suggest that the adult mouse CP is a source of factor(s) that inhibits tumor formation and induce a catecholaminergic neuronal phenotype in these human NT2 cells in vivo and in vitro. Identification of these factors could accelerate efforts to elucidate mechanisms that regulate progenitor cell fate and the commitment of neurons to specific neurotransmitter phenotypes.

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Tissue storage prior to intracerebral transplantation would represent a major advantage when conducting clinical transplantation trials in that the procurement of the embryonic donor tissue and the timing of neurosurgery could be planned more efficiently. In the present study, the effects of storing rat embryonic striatal tissue at either +4 degrees C or below freezing temperature prior to grafting to the adult striatum, were assessed with regard to transplant survival, morphology and integration. Eleven days following a unilateral injection of ibotenic acid into the head of the caudate-putamen, a control group of rats received grafts of striatal primordium prepared immediately after dissection from rat embryos (embryonic day 16). A second group of rat embryonic striatal tissue was stored at 4 degrees C (hibernation) for 5 days and then transplanted. A third group of the striatal donor tissue was cryopreserved in liquid nitrogen for 5 days before implantation surgery. Six to seven weeks following transplantation surgery, the grafts were analysed in brain sections processed for acetylcholinesterase histochemistry, DARPP-32 (dopamine and cyclic AMP regulated phosphoprotein with a molecular weight of 32 kDa) and tyrosine hydroxylase (TH) immunocytochemistry. The mean total graft volume and the relative size of the AChE-positive regions were not significantly different between the three groups. Striatal-specific graft regions, positively stained for AChE and DARPP-32, generally exhibited TH immunoreactivity, suggesting that they had received dopaminergic afferents from the host brain. We conclude that embryonic rat striatal tissue can be cryopreserved or hibernated over 5 days without significant impairment in the yield of striatal neurons following intrastriatal implantation and without markedly affecting transplant morphology.

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Dendritic spine density was determined quantitatively in 35-day-old neostriatal transplants and age-matched control tissue. Transplanted spiny I neurons showed significant decreases in spine density and in number of proximal dendrites. These differences may be due to aberrant maturation of transplanted neurons.

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The afferent and efferent connections of grafts of fetal caudate-putamen, implanted into the ibotenic acid (IA)-lesioned striatum of adult rats, have been studied with wheat germ agglutinin conjugated horseradish peroxidase (WGA-HRP) as a combined retrograde and anterograde tracer, and with aldehyde fluorescence histochemistry for the visualisation of dopamine-containing nigrostriatal afferents from the host. The WGA-HRP was deposited in crystalline form (within a capillary tip) either into the depth of the graft tissue, or into the IA lesioned host striatum as a control. Labelling was only evaluated in specimens where the WGA-HRP deposit was entirely confined within the graft. Retrogradely labelled neurons were most consistently found in the ipsilateral host substantia nigra and the spared portions of the host CP, and in one case also in the midline and intralaminar thalamic nuclei normally projecting to the striatum. Some neurons, although weakly labelled, occurred in the deep layers of the frontal cortex in all grafted rats. Signs of anterograde WGA-HRP labelling in the host were found in one of the five animals in the ipsilateral globus pallidus and substantia nigra, pars reticulata. Fluorescence histochemistry revealed extensive ingrowth of dopamine-containing fibres from the host striatum into the grafted striatal tissue. The ingrowing fibres formed distinct and partly interconnected patches, most prominently in the peripheral regions of the grafts. The results provide evidence that intrastriatal grafts of fetal striatal tissue receive extensive dopaminergic afferents from the host substantia nigra, and that they may be capable of establishing connections also with thalamus, neocortex and globus pallidus of the host, as well as with the spared portions of the host caudate-putamen. The afferent connections from the thalamus and neocortex were notably more variable and sparse. However, since the control WGA-HRP deposits (into the lesioned host striatum) labelled the cortical and thalamic afferent neurons only poorly, it appears that the cortico-striatal and thalamo-striatal afferents (in contrast to the nigro-striatal ones) had undergone substantial degenerative changes (atrophy and/or cell death) in the long-term (6-11 months) IA-lesioned rats. The sparse thalamic and cortical afferent connections to the grafts may thus reflect an inability of the grafted striatal tissue to prevent the course of degenerative changes in these striatal input systems.

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